Project Summary/Abstract Chronic pancreatitis affects more than 140,000 individuals in the United States alone, and millions world-wide. Therapeutic interventions for chronic pancreatitis typically involve either relatively ineffective pain treatments, or highly invasive and morbid surgical procedures. Chronic pancreatitis entails severe, chronic debilitating pain, along with potentially life-threatening complications such as pseudocyst, pancreatic ascites, biliary obstruction, etc. Chronic pancreatitis patients have a roughly 13-fold increased risk of developing pancreatic ductal adenocarcinoma. Furthermore, unfortunately most chronic pancreatitis patients go on to develop a very brittle form of diabetes mellitus, type 3c, in which they lose not only insulin cells, but all islet cells, so that they lose important insulin counter-regulatory mechanisms. It appears that the ongoing chronic exocrine damage creates a toxic milieu for the islet cells. This toxic milieu leads to progressive islet cell dysfunction and islet cell loss. One therapeutic strategy for these patients is a total pancreatectomy with islet autotransplantation. This procedure is highly morbid, and more than half of the original islets can be lost. In addition, the autotransplanted islets are situated in the liver, where beta cell function is significantly diminished compared to their function in situ within the pancreas. Recently, we serendipitously found that an infusion of either ethanol or acetic acid into the pancreatic duct of mice led to complete ablation of the acini and ducts, but the islets were completely spared, and functioned normally and indefinitely. We then turned to a mouse model of chronic pancreatitis that mimics the human condition in that the islets are lost over time. Remarkably, by intervening with an ethanol or acetic acid infusion in mice with well-established chronic pancreatitis, but prior to significant islet loss, we saw complete and durable protection of the islet mass. Lastly, we developed a pancreatic duct infusion system in non- human primates that has allowed for preliminary success with a similar exocrine ablation, and with islet preservation. Here, in this proposal we wish to better understand what the infusion is doing to the pancreas. Specifically, a detailed analysis of innervation (with a focus on pain pathways and peripheral and central pain sensitization), immune cells and inflammation, and the effect on pain experienced. We will try to understand how and why the islets are spared, perhaps related to the islet ?capsule? that has been recently described. We will also strive to build on our preliminary attempts to optimize this chemical pancreatectomy in non-human primates to bring us closer to therapeutic trials in human subjects. Lastly, with the high risk of pancreatic cancer in chronic pancreatitis patients, we will determine what effect ethanol or acetic acid infusion may have on pre-cancerous lesions and cancers of the pancreas in mice.